PROJECT SUMMARY Dementia with Lewy bodies and Parkinson?s disease are characterized pathologically by the presence of Lewy bodies, composed of misfolded alpha synuclein (?-syn) inclusions. These disorders are progressive, and result from the degeneration of dopaminergic neurons in multiple motor and non-motor basal ganglia circuits. While the current gold standard treatment for PD is dopamine replacement therapy, and addresses motor dysfunction, over time it ultimately results in motor fluctuations and dyskinesias. Surgical therapies such as deep brain stimulation (DBS) can alleviate some of these symptoms in select patients, but do not alter disease course. Hence there is an unmet need of lack of viable treatments to slow down progression of syncleinopathies such as LBD and PD. Furthermore, there is a lack of sensitive and objective real-time markers of disease progression, for use in clinical trials. In this proposal, we begin to target ?-syn deposition and neuronal death via a unique, immunomodulatory approach in Aim 1. We will combine this novel therapeutic approach with high-resolution in vivo neuroimaging in Aim 2 to determine whether reducing neuroinflammation limits microstructural changes in wide-spread neuronal networks while concurrently decreasing ?-syn burden. Ultimately, findings from this innovative and novel study will pave the way for applying immunomodulatory therapies to Lewy body dementias and other synucleinopathies.